Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1

• Published in: Cell Vol. 175; no. 4; pp. 947 - 961.e17
• Main Authors: Koh, Ara, Molinaro, Antonio, Ståhlman, Marcus, Khan, Muhammad Tanweer, Schmidt, Caroline, Mannerås-Holm, Louise, Wu, Hao, Carreras, Alba, Jeong, Heeyoon, Olofsson, Louise E., Bergh, Per-Olof, Gerdes, Victor, Hartstra, Annick, de Brauw, Maurits, Perkins, Rosie, Nieuwdorp, Max, Bergström, Göran, Bäckhed, Fredrik
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2018
• Subjects: 1991; activation; amino-acids; autophosphorylation; Biochemistry & Molecular Biology; Cell Biology; Cellbiologi; diet; disease; glucose tolerance; gut microbiota; histidine; hroder i; iences; imidazole propionate; insulin; insulin receptor substrate proteins; intestinal microorganisms; IRS; journal of biological chemistry; liver; metabolites; mice; microbiome; mitogen-activated protein kinase; Molecular Biology; Molekylärbiologi; mTORC1; noninsulin-dependent diabetes mellitus; obesity; p1218; p13572; p38γ; p62; pathogenesis; pathway; phosphorylation; protein; rapamycin; receptor substrate-1; serum metabolome; v266; v66; imidazole propionate; IRS; microbiome; p38γ; mTORC1; p62; histidine
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2018.09.055

Interactions between the gut microbiota, diet, and the host potentially contribute to the development of metabolic diseases. Here, we identify imidazole propionate as a microbially produced histidine-derived metabolite that is present at higher concentrations in subjects with versus without type 2 diabetes. We show that imidazole propionate is produced from histidine in a gut simulator at higher concentrations when using fecal microbiota from subjects with versus without type 2 diabetes and that it impairs glucose tolerance when administered to mice. We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1). We also demonstrate increased activation of p62 and mTORC1 in liver from subjects with type 2 diabetes. Our findings indicate that the microbial metabolite imidazole propionate may contribute to the pathogenesis of type 2 diabetes. [Display omitted] •Imidazole propionate levels are increased in subjects with type 2 diabetes (T2D)•Imidazole propionate is produced from histidine by T2D-associated bacteria•Imidazole propionate impairs glucose tolerance and insulin signaling•Imidazole propionate inhibits IRS via activation of p38γ/p62/mTORC1 Imidazole propionate, a metabolite produced by the gut microbiota, is elevated in type 2 diabetes and can directly impair glucose tolerance and insulin signaling.